Camptothecin is an alkaloid, which was isolated by Wall et al (J. Am. Chem. Soc. 88, 3888-3890 (1966)) for the first time from the tree Camptoteca acuminata, a plant originating from China, of the Nyssaceae family. The molecule consists of a pentacyclic structure having a lactone in the E ring, which is essential for cytotoxicity. The drug demonstrated a wide spectrum of antitumor activity, in particular against colon tumors, other solid tumors and leukemias, and the first clinical trials were performed in the early 70's.
Since Camptothecin (CPT) has low water solubility and in order to prepare clinical trials, the National Cancer Institute (NCI) prepared the sodium salt (NSC100880), which is water-soluble. Clinical trials in phase I and II were not completed because of the high toxicity showed by the compound (hemorrhagic cystitis, gastrointestinal toxicity, such as nausea, vomit, diarrhoea, and myelosuppression, especially leucopenia and thrombocytopenia.
Subsequently, many CPT analogues were synthesised in order to obtain compounds with lower toxicity and higher water solubility. Two drugs are marketed, irinotecan (CPT-11) (Camptosar™ by Upjohn) and topotecan (Hycamtin™ or Thycantin™ by Smith Kline & Beecham). All the derivatives identified to-date contain the parent structure with 5 rings, essential for cytotoxicity. It was demonstrated that modifications on the first ring, such as in the case of the above-mentioned drugs increase water solubility and allow a higher tolerability of the drug.
Patent application WO97/31003 discloses derivatives of camptothecins substituted at positions 7, 9 and 10. Position 7 provides the following substitutions: —CN, —CH(CN)—R4, —CH═C(CN)—R4, —CH2—CH═C(CN)—R4, —C(═NOH)—NH2, —CH═C(NO2)—R4, —CH(CH2NO2)—R4, 5-tetrazolyl, 2-(4,5-dihydroxazolyl), 1,2,4-oxadiazolidin-3-yl-5-one, wherein R4 is hydrogen, linear or branched alkyl from 1 to 6 carbon atoms, nitrile, carboxyalkoxy.
Of these compounds, the best one proved to be the 7-nitrile (7-CN), hereinafter named CPT 83, with cytotoxic activity on non-small cells lung carcinoma (non-SCLC, H-460). This tumour line is intrinsically resistant to cytotoxic therapy and is only moderately responsive to topoisomerase I inhibitors, notwithstanding the over-expression of the target enzyme. CPT 83 is more active than topotecan, taken as reference compound and on the whole it offers a better pharmacological profile, even in terms of tolerability, then a better therapeutic index.
CPT 83 is prepared trough a synthesis route comprising the oxidation of 7-hydroxymethylcamptothecin to camptothecin 7-aldehyde, the transformation of the latter into oxime and final conversion into nitrile.
The starting compound and the intermediates are disclosed in Sawada et al., Chem. Pharm. Bull., 39, 5272 (1991). This paper makes reference to a patent family with priority of 1981, for example European patent application EP 0056692, published in 1982. In these publications camptothecin 7-aldehyde and its oxime are described among others.
The usefulness of these derivatives is to provide compounds with antitumor activity having low toxicity starting from 7-hydroxymethylcamptothecin. In the paper published on Chem. Pharm. Bull. 39, 5272 (1991), the authors demonstrate that, with respect to camptothecin, the 7-alkyl and 7-acyloxymethyl derivatives, which were not foreseen in the above mentioned patent application, are the more active compounds on lines of murine leukemia L1210, while lower activity, always with respect to camptothecin, was observed in compounds bearing 7-substitutions with high polar character, such as hydrazones and the oxime —CH(═NOH).
In patent application EP1044977 and in Dallavalle S. et al., J. Med. Chem. 2001, 44, 3264-3274, camptothecin derivatives are described which bear an alkyloxime O-substituted at position 7 and which are endowed with antitumor activity higher than the compound of reference topotecan. Moreover these camptothecin derivatives bearing an imino group on position 7, also show an improved therapeutic index. Among these compounds one of the preferred molecules was shown to be 7-t-butoxyiminomethylcamptothecin (CPT 184). When this molecule is prepared as described in EP1044977 and in the above Dallavalle paper, a mixture of the two E and Z isomers, in 8:2 ratio, is obtained from a solvent mixture containing ethanol and pyridine.
All the processes described in the above-mentioned literature for obtaining camptothecin derivatives bearing alkyloxime O-substituted at position 7 lead to a mixture of the two E and Z isomers of the oxime or the alkyloxime.
Therefore, it is desirable to make available a stereoselective process leading to single E,Z isomers, respectively, more particularly the E isomer.
Many drugs, old and new, were discovered and rushed into market as their ‘suitable’ crystalline forms and had never been screened thoroughly for their potential polymorphic forms. With the recent technological advancement of solid state chemistry, it is possible that new polymorphic forms can be discovered, which have never been seen before. The new polymorphic forms are often able to deliver therapeutic advantages and represent one of the new challenges of the pharmaceutical industry. As a matter of fact polymorphism, the ability of a molecule to crystallize into more than one crystal arrangement, can have a profound effect on the shelf life, solubility, formulation properties, and processing properties of a drug. More seriously, the action of a drug can be affected by the polymorphism of the drug molecules. Different polymorphs can have different rates of uptake in the body, leading to lower or higher biological activity than desired. In extreme cases, an undesired polymorph can even be toxic. The occurrence of an unknown polymorphic form during manufacture can have an enormous impact on a drug company. Therefore it is vital that researchers involved in the formulation of crystalline products be able to select the polymorph with the correct properties and anticipate problems such as the unwanted crystallization of other polymorphs. Surprisingly, a very large number of pharmaceuticals exhibit the phenomenon of polymorphism. 70% of barbiturates, 60% of sulfonamides and 23% of steroids exist in different polymorphic forms.
The problem of polymorphism in organic compounds is generically reviewed by Caira, M. R. “Crystalline Polymorphism of Organic Compounds”, Topics in Current Chemistry, Springler, Berlin, Del., Vol. 198, 1998, pages 163-208.
Conducting a crystallization study on gimatecan has brought the Applicant to the claimed invention.